EP4396193A1 - Analogues de n-acétylgalactosamine fonctionnalisés - Google Patents

Analogues de n-acétylgalactosamine fonctionnalisés

Info

Publication number
EP4396193A1
EP4396193A1 EP22865693.0A EP22865693A EP4396193A1 EP 4396193 A1 EP4396193 A1 EP 4396193A1 EP 22865693 A EP22865693 A EP 22865693A EP 4396193 A1 EP4396193 A1 EP 4396193A1
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
independently
optionally substituted
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22865693.0A
Other languages
German (de)
English (en)
Inventor
Wing C. POON
Gang Zhao
Gengyu DU
Yun-Chiao YAO
Mufa ZOU
Xiaoyang GUAN
Xiaoling Zheng
David Yu
Ruiming Zou
Aldrich N.K. Lau
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hongene Biotech Corp
Original Assignee
Hongene Biotech Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hongene Biotech Corp filed Critical Hongene Biotech Corp
Publication of EP4396193A1 publication Critical patent/EP4396193A1/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical

Definitions

  • the present application relates to functionalized N-acetylgalactosamine analogs and their methods of preparation. More specifically, the present application relates to compounds having N-acetylgalactosamine moieties conjugated to a moiety having multiple functional groups using a variety of linkers.
  • the functionalized N-acetylgalactosamine analogs disclosed herein may be used for targeted in vivo delivery of oligonucleotide-based therapeutics.
  • REFERENCE TO SEQUENCE LISTING [0002] The present application is being filed along with a Sequence Listing in electronic format.
  • ASGPR consists of two homologous subunits, designated H1 and H2 in the human system, which form a non-covalent heterooligomeric complex with estimated ratios of 2:1 and 5:1, respectively.
  • Both subunits are single-spanning membrane proteins with a calcium-dependent Gal/GalNAc recognition domain (CRDs). On the native receptor on the hepatocyte surface these binding sites are 25-30 ⁇ apart. All conjugations of mono-, di-, tri-, or tetra-GalNAc sugars can enhance the delivery efficiency of oligonucleotides to hepatocytes. Binding hierarchy of polyvalent ligands is : tetraantennary > triantennary >>diantennary >> monoantennary.
  • compounds of Formula (II) have the structure of Formula (IIa): or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (II) have the structure of Formula (IIb):
  • a further aspect of the present disclosure relates to a solid support comprising a compound described herein of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc) or (IId) covalently attached thereto via R 6 .
  • the compound is covalently attached to the solid support via a moiety: wherein the dashed line refers to the connection with the solid support, optionally through an additional linker, and wherein the squiggly line refers to the point of the attachment of the oxygen atom that covalently attached to R 6 of the compound, to the remaining portion of the compound.
  • Additional aspect of the present disclosure relates to a method of preparing a synthetic oligonucleotide, comprising reacting a compound described herein of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc) or (IId) with an oligonucleotide.
  • the oligonucleotide may have a 1 to 100 nucleobase length.
  • the reaction may be conducted on a solid support.
  • DETAILED DESCRIPTION [0016] The compounds disclosed herein relate to novel functionalized GalNAc analogs to provide novel methods for oligonucleotide delivery.
  • the functionalized GalNAc analogs disclosed herein may contain a phosphoramidite moiety that allows for the incorporation of the GalNAc analogs to the 5’ end or any internal position of an oligonucleotide.
  • the functionalized GalNAc analogs disclosed herein may contain a succinate moiety that allows for the incorporation of the GalNAc analogs on a solid support, which can introduce GalNAc analogs described herein to the 3’ end of oligonucleotide.
  • any “R” group(s) represent substituents that can be attached to the indicated atom.
  • An R group may be substituted or unsubstituted. If two “R” groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, aryl, heteroaryl, or heterocycle.
  • R a and R b and the atom to which it is attached, are indicated to be “taken together” or “joined together” it means that they are covalently bonded to one another to form a ring:
  • R a and R b and the atom to which it is attached, are indicated to be “taken together” or “joined together” it means that they are covalently bonded to one another to form a ring:
  • substituent may be selected from one or more of the indicated substituents.
  • the indicated “optionally substituted” or “substituted” group may be one or more group(s) individually and independently selected from alkyl (e.g., C 1 -C 6 alkyl); alkenyl (e.g., C 2 -C 6 alkenyl); alkynyl (e.g., C 2 -C 6 alkynyl); C 3 -C 8 carbocyclyl (for example, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, or C 3 -C 8 cyclalkynyl, each may further be optionally substituted, for example, with halo, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, or -O(C 1 -C 6 alkyl, or -O
  • C a to C b or “C a to b ” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl group, or the number of ring atoms of a cycloalkyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, ring of the cycloalkyl, and ring of the aryl, can contain from “a” to “b”, inclusive, carbon atoms. Likewise, the ring of the heteroaryl and ring of the heterocyclyl can contain from “a” to “b”, inclusive, total ring atoms.
  • a “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2- , CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-;
  • a C 3 to C 4 cycloalkyl group refers to all cycloalkyl groups having from 3 to 4 carbon atoms, that is, cyclopropyl and cyclobutyl.
  • C 1 -C 6 alkyl includes C 1 , C 2 , C 3 ,C 4 , C 5 and C 6 alkyl, C 2 -C 6 alkyl, C 1 -C 3 alkyl, etc.
  • C 3 -C 8 carbocyclyl or cycloalkyl each includes hydrocarbon ring containing 3, 4, 5, 6, 7 and 8 carbon atoms, or a range defined by any of the two numbers, such as C 3 -C 7 cycloalkyl or C 5 -C 6 cycloalkyl.
  • alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group of the compounds may be designated as “C 1 -C 4 alkyl” or similar designations.
  • “C 1 -C 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • alkyl groups include, but are in no way limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl (straight chain or branched), and hexyl (straight chain or branched).
  • the alkyl group may be substituted or unsubstituted.
  • alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms.
  • alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted.
  • alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds.
  • the alkynyl group may have 2 to 20 carbon atoms.
  • C 2 -C 4 alkynyl indicates that there are two to six carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn- 2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl.
  • Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
  • alkynyl group may be substituted or unsubstituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
  • fused refers to two rings which have two atoms and one bond in common.
  • bridged cycloalkyl refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms.
  • bicyclic fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bicyclic bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; and examples of bicyclic spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane. [0029] As used herein, “carbocyclyl” refers to a non-aromatic a mono- or multi- cyclic hydrocarbon ring system.
  • aryl group can be a C6 aryl group, or a C 10 aryl group.
  • aryl groups include, but are not limited to, benzene and naphthalene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,
  • heteroaryl group may be substituted or unsubstituted.
  • heterocyclyl refers to three-, four-, five-, six-, seven-, eight-, nine-, and ten-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings (i.e., heterocyclyl groups are not aromatic).
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
  • Heterocyclyl groups can be linked to the rest of the molecule via a carbon atom in the heterocyclyl group (C- linked) or by a heteroatom in the heterocyclyl group, such as a nitrogen atom (N-linked). Heterocyclyl groups may be unsubstituted or substituted.
  • spiro heterocyclyl groups examples include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2- oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.
  • alkylene refers to a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogen that is attached to the rest of the molecule via two points of attachment.
  • alkylene is an unsubstituted straight chain containing 1, 2, 3, 4, 5, or 6 methylene unit(s).
  • (heterocyclyl)alkyl refer to a heterocyclic or a heterocyclyl group, as defined above, connected, as a substituent, via an alkylene group, as defined above.
  • the alkylene and heterocyclyl groups of a (heterocyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited to (tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and (1,3-thiazinan-4-yl)methyl.
  • the alkylene is an unsubstituted straight chain containing 1, 2, 3, 4, 5, or 6 methylene unit(s).
  • haloalkyl refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri- haloalkoxy).
  • An O-carboxy may be substituted or unsubstituted.
  • a “trihalomethanesulfonyl” group refers to an “X3CSO2-“group wherein X is a halogen.
  • a “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(R)-” group wherein X is a halogen and R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), as defined herein.
  • a “mercapto” group refers to an “-SH” group.
  • N-sulfonamido refers to a “RSO2N(RA)-“ group in which R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), as defined herein.
  • R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), as defined herein.
  • An N-sulfonamido may be substituted or unsubstituted.
  • Each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium).
  • hydrogen- 1 protium
  • hydrogen-2 deuterium
  • tritium tritium
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Other forms in which the compounds of preferred embodiments can be provided include amorphous forms, milled forms and nano- particulate forms.
  • Trivalent GalNAc Analogs of Formula (II) [0095] Some embodiments provide a compound of Formula (II), or a pharmaceutically acceptable salt thereof as described herein:
  • R 7 is an amino protecting group, e.g., a Cbz group.
  • R Z is H.
  • R Z is C1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl.
  • L 5 may comprise 3 to 15 membered heteroalkylene comprising 1-5 units of PEG (i.e., L 5 is –(CH2CH2O)–1-5).
  • R 5 is a trityl type hydroxy protecting group.
  • R 5 is (4- methoxyphenyl)diphenylmethyl (i.e., monomethoxytrityl (MMTr)).
  • MMTr monomethoxytrityl
  • R 5 is bis(4-methoxyphenyl)phenylmethyl (i.e., 4,4’-dimethoxytrityl (DMTr)).
  • R 5 is tris(4-methoxyphenyl)methyl (i.e., 4,4’,4”-trimethoxytrityl (TMTr)). In further embodiments, R 5 is 9-phenylxanthen-9-yl or 9-(4-methoxyphenyl)xanthen-9-yl. [0102] In some embodiments of the compounds of Formula (II), (IIa), (IIb) or (IIIc), R 6 is hydrogen. In other embodiments, R 6 is a phosphoramidite moiety.
  • Step 2 Coupling [0113] A 0.02–0.2M solution of nucleoside phosphoramidite (or a mixture of several phosphoramidites) in acetonitrile is activated by a 0.2–0.7 M solution of an acidic azole catalyst, 1H-tetrazole, 5-ethylthio-1H-tetrazole, 2-benzylthiotetrazole, 4,5-dicyanoimidazole, or a number of similar compounds.
  • the mixing is usually very brief and occurs in fluid lines of oligonucleotide synthesizers (see below) while the components are being delivered to the reactors containing solid support.
  • the activated phosphoramidite in 1.5 – 20-fold excess over the support-bound material is then brought in contact with the starting solid support (first coupling) or a support-bound oligonucleotide precursor (following couplings) whose 5'-hydroxy group reacts with the activated phosphoramidite moiety of the incoming nucleoside phosphoramidite to form a phosphite triester linkage.
  • the reaction is also highly sensitive to the presence of water, particularly when dilute solutions of phosphoramidites are used, and is commonly carried out in anhydrous acetonitrile.
  • Step 3 Capping [0114]
  • the capping step is performed by treating the solid support-bound material with a mixture of acetic anhydride and 1-methylimidazole or, less often, DMAP as catalysts and, in the phosphoramidite method, serves two purposes.
  • a small percentage of the solid support-bound 5'-OH groups (0.1 to 1%) remains unreacted and needs to be permanently blocked from further chain elongation to prevent the formation of oligonucleotides with an internal base deletion commonly referred to as (n-1) shortmers.
  • the unreacted 5'-hydroxy groups are, to a large extent, acetylated by the capping mixture.
  • Step 4 Oxidation [0115]
  • the newly formed tricoordinated phosphite triester linkage is not natural and is of limited stability under the conditions of oligonucleotide synthesis.
  • the treatment of the support-bound material with iodine and water in the presence of a weak base (pyridine, lutidine, or collidine) oxidizes the phosphite triester into a tetracoordinated phosphate triester, a protected precursor of the naturally occurring phosphate diester internucleosidic linkage.
  • a weak base pyridine, lutidine, or collidine
  • the solid support is contained in columns whose dimensions depend on the scale of synthesis and may vary between 0.05 mL and several liters.
  • the oligonucleotide is released from the solid support and is eluted from the column or the well.
  • the two most often used solid-phase materials are controlled pore glass (CPG) and macroporous polystyrene (MPPS).
  • CPG controlled pore glass
  • MPPS macroporous polystyrene
  • CPG is commonly defined by its pore size. In oligonucleotide chemistry, pore sizes of 500, 1000, 1500, 2000, and 3000 ⁇ are used to allow the preparation of about 50, 80, 100, 150, and 200-mer oligonucleotides, respectively.
  • the surface of the material is treated with (3-aminopropyl)triethoxysilane to give aminopropyl CPG.
  • the aminopropyl arm may be further extended to result in long chain aminoalkyl (LCAA) CPG. The amino group is then used as an anchoring point for linkers suitable for oligonucleotide synthesis.
  • LCAA long chain aminoalkyl
  • Step 1 GalNAc (10 g, 25.7 mmol) and Compound 1 (15.4 g, 102.7 mmol) were dissolved in DCM (100 mL) and CF 3 SO 3 H (0.34 mL, 3.85 mmol) was then added. The reaction mixture was reflux under argon overnight and then cooled down to rt. This mixture was then poured into 1 M NaHCO3 (51 mL), and the organic layer was separated, washed with water, brine and dried over Na s SO 4 . After filtration, the organic layer was concentrated to dryness under vacuum.
  • Compound 20 Compound 18 (1.64 g, 3.48 mmol) was dissolved in DCE (37 mL), and TEA (2.2 mL) was added followed by HATU (5.29 g, 13.9 mmol). This solution was allowed to stir at room temperature for 1 h. A solution of Compound 19 in DCE (37 mL) and TEA (2.2 mL) was added to the activated acid solution. This reaction mixture was stirred at room temperature overnight. Water (100 mL) was added to the reaction mixture with vigorous stirring. The organic phase was separated, and the aqueous phase was extracted with DCM (2 x 50 mL).
  • the CPG was washed with THF (50 mL x 3), 10% pyridine in EtOH (50 mL x 3), EtOH (50 mL x 3), acetonitrile (50 mL x 3) and MTBE (50 mL x 3) successively.
  • the CPG was dried under reduced pressure overnight to give the compound 34 (21 g, Loading was determined by standard DMTr assay by UV-Vis (498 nm) to be 54 ⁇ mol/g). Ninhydrin test: negative.
  • Example 7 Preparation of monovalent GalNAc analogs Compounds 40 and 41 Scheme 7.
  • Compound 36 In a 50 mL round bottom flask, oxalyl chloride (0.64 g, 5.0 mmol) was dissolved in DCM (10 mL) at -78 o C under argon atmosphere. DMSO (078 g, 10.01 mmol) was added dropwise. The mixture was stirred at -78 o C for 20 minutes. Compound 35 in DCM (4.0 mL) was added dropwise, the mixture was stirred at -78 o C for 15 minutes, and then Et3N (2.02 g) was added dropwise, the mixture was stirred at -78 o C for 60 minutes.
  • the standard synthetic cycle useful in assembling oligonucleotides comprise the steps of: (a) detritylation of the solid phase-bound material; (b) coupling of nucleoside phosphoramidite building block required by the sequence to the solid support-bound material in the presence of coupling agent; (c) capping of unreacted solid support-bound hydroxy groups with a mixture of acetic anhydride and N-methyl imidazole and (d) oxidation of the solid support- bound phosphite triester groups.
  • the cycle appropriate for the assembly of the desired oligonucleotide was repeated as required by the sequence in preparation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

Des modes de réalisation de la présente invention concernent des analogues de N-acétylgalactosamine fonctionnalisés, leurs procédés de fabrication et leurs utilisations. En particulier, des analogues de N-acétylgalactosamine monovalents ou trivalents peuvent être préparés en utilisant une grande diversité de lieurs contenant des groupes fonctionnels. Ces analogues de N-acétylgalactosamine fonctionnalisés peuvent être utilisés dans la préparation d'une administration ciblée d'agents thérapeutiques à base d'oligonucléotides.
EP22865693.0A 2021-08-30 2022-08-26 Analogues de n-acétylgalactosamine fonctionnalisés Pending EP4396193A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163238561P 2021-08-30 2021-08-30
PCT/US2022/075495 WO2023034719A1 (fr) 2021-08-30 2022-08-26 Analogues de n-acétylgalactosamine fonctionnalisés

Publications (1)

Publication Number Publication Date
EP4396193A1 true EP4396193A1 (fr) 2024-07-10

Family

ID=85411590

Family Applications (1)

Application Number Title Priority Date Filing Date
EP22865693.0A Pending EP4396193A1 (fr) 2021-08-30 2022-08-26 Analogues de n-acétylgalactosamine fonctionnalisés

Country Status (5)

Country Link
US (2) US11692001B2 (fr)
EP (1) EP4396193A1 (fr)
JP (1) JP2024532271A (fr)
CN (1) CN118434751A (fr)
WO (1) WO2023034719A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4396193A1 (fr) 2021-08-30 2024-07-10 Hongene Biotech Corporation Analogues de n-acétylgalactosamine fonctionnalisés
WO2023114746A1 (fr) 2021-12-15 2023-06-22 Hongene Biotech Corporation Analogues de n-acétylgalactosamine fonctionnalisés
WO2024104386A1 (fr) * 2022-11-16 2024-05-23 南京明德新药研发有限公司 Classe de groupes conjugués tridentés comprenant un hétérocycle à sept chaînons
WO2024118503A1 (fr) 2022-11-28 2024-06-06 Hongene Biotech Corporation Analogues de n-acétylgalactosamine fonctionnalisés
EP4444357A1 (fr) * 2022-12-19 2024-10-16 Arnatar Therapeutics, Inc Composés arnatar et méthodes pour absorption cellulaire améliorée

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002351077A1 (en) 2001-11-05 2003-05-19 Exiqon A/S Oligonucleotides modified with novel alpha-l-rna analogues
US7037936B2 (en) 2002-06-17 2006-05-02 Signal Pharmaceuticals, Llc. Compounds useful for the treatment of cancer, compositions thereof and methods therewith
CA2737661C (fr) 2008-09-23 2019-08-20 Alnylam Pharmaceuticals, Inc. Modifications chimiques de monomeres et d'oligonucleotides par cycloaddition
MX342609B (es) 2010-12-29 2016-10-06 Hoffmann La Roche Conjugados de molecula pequeña para suministro intracelular de acidos nucleicos.
EP2663314A2 (fr) 2011-01-11 2013-11-20 The University of Texas M.D. Anderson Cancer Composés à base de monosaccharides pour le traitement de maladies dermatologiques prolifératives et inflammatoires
GB201214736D0 (en) 2012-08-17 2012-10-03 Isis Innovation Inflammation imaging and therapy
EP3004131B1 (fr) 2013-06-05 2020-07-22 AM Chemicals Llc Blocs de construction à base de phosphoramidite pour oligonucléotides conjugués à des sucres
WO2015066001A1 (fr) 2013-10-29 2015-05-07 Albert Einstein College Of Medicine Of Yeshiva University Bibliothèques de petites molécules à squelette d'acide nucléique
WO2015066697A1 (fr) 2013-11-04 2015-05-07 Forum Pharmaceuticals Inc. Morpholinopyrimidines fusionnées et procédés d'utilisation de ces dernières
JP6482475B2 (ja) 2014-01-07 2019-03-13 レナセラピューティクス株式会社 アンチセンスオリゴヌクレオチド及び糖誘導体を含む二本鎖オリゴヌクレオチド
KR102149571B1 (ko) * 2014-05-01 2020-08-31 아이오니스 파마수티컬즈, 인코포레이티드 성장 호르몬 수용체 발현을 조절하기 위한 조성물 및 방법
EP3291828A4 (fr) 2015-05-06 2018-10-03 Alborz Mahdavi Insulines sensibles au glucose
JOP20210043A1 (ar) 2015-10-01 2017-06-16 Arrowhead Pharmaceuticals Inc تراكيب وأساليب لتثبيط تعبير جيني للـ lpa
WO2017066789A1 (fr) 2015-10-16 2017-04-20 Modernatx, Inc. Analogues de coiffe d'arnm avec sucre modifié
EP3362460A1 (fr) 2015-10-16 2018-08-22 Modernatx, Inc. Analogues de coiffes arnm et procédés de coiffage d'arnm
WO2017066797A1 (fr) 2015-10-16 2017-04-20 Modernatx, Inc. Analogues de coiffes d'arnm trinucléotidiques
MA45478A (fr) 2016-04-11 2019-02-20 Arbutus Biopharma Corp Compositions de conjugués d'acides nucléiques ciblés
EP3484908A4 (fr) 2016-07-15 2020-04-08 AM Chemicals Llc Supports solides non nucléosides et blocs de construction de phosphoramidite pour synthèse d'oligonucléotides
JP6989521B2 (ja) 2016-09-02 2022-01-05 アローヘッド ファーマシューティカルズ インコーポレイテッド 標的化リガンド
KR20190065341A (ko) 2016-10-06 2019-06-11 아이오니스 파마수티컬즈, 인코포레이티드 올리고머 화합물들의 접합 방법
WO2019051257A2 (fr) * 2017-09-11 2019-03-14 Arbutus Biopharma Corporation Méthodes de traitement des infections de type hépatite b
JP2020533009A (ja) 2017-09-14 2020-11-19 ヤンセン バイオファーマ インク． ＧａｌＮＡｃ誘導体
KR102609396B1 (ko) 2017-10-13 2023-12-01 노보 노르디스크 헬스 케어 악티엔게젤샤프트 Ldha의 발현을 억제하기 위한 방법 및 조성물
AU2017444369B2 (en) * 2017-12-26 2022-02-24 Guangzhou Ribobio Co., Ltd. Modified oligonucleotides and compound that can be used for synthesizing same
US11958878B2 (en) * 2018-03-09 2024-04-16 Daiichi Sankyo Company, Limited Therapeutic agent for glycogen storage disease type IA
GB201807040D0 (en) 2018-04-30 2018-06-13 Univ Oxford Innovation Ltd Drug delivery
US10820022B1 (en) 2018-05-03 2020-10-27 Amazon Technologies, Inc. Low latency playback for chunked media segments
AU2019370563A1 (en) 2018-11-02 2021-05-27 Genevant Science GmbH Therapeutic methods
JP2022507118A (ja) 2018-11-07 2022-01-18 ザ ユニヴァーシティー オブ メルボルン 呼吸器疾患の処置のための化合物及び組成物
CN113891892B (zh) 2019-08-29 2024-01-30 苏州瑞博生物技术股份有限公司 化合物和药物缀合物及其制备方法和用途
BR112022027052A2 (pt) 2020-09-11 2023-04-11 Illumina Inc Detecção de elementos com o uso de acoplamentos de açúcar-lectina
KR20230113285A (ko) 2020-10-09 2023-07-28 아다르엑스 파마슈티컬스, 인크. N-아세틸갈락토사민(GAlNAc)-유래 화합물 및 올리고뉴클레오티드
CN117836307A (zh) 2021-06-18 2024-04-05 弘景生物科技有限公司 功能化的n-乙酰基半乳糖胺核苷
EP4396193A1 (fr) 2021-08-30 2024-07-10 Hongene Biotech Corporation Analogues de n-acétylgalactosamine fonctionnalisés

Also Published As

Publication number Publication date
WO2023034719A1 (fr) 2023-03-09
US20230100220A1 (en) 2023-03-30
US11692001B2 (en) 2023-07-04
US20230340000A1 (en) 2023-10-26
JP2024532271A (ja) 2024-09-05
US11884691B2 (en) 2024-01-30
CN118434751A (zh) 2024-08-02

Similar Documents

Publication Publication Date Title
US11692001B2 (en) Functionalized n-acetylgalactosamine analogs
US11649260B2 (en) Functionalized N-acetylgalactosamine nucleosides
AU2017251107B9 (en) Targeted nucleic acid conjugate compositions
ES2479393T3 (es) Método de síntesis de oligómeros de morfolino
JP5685526B2 (ja) ヌクレオシドの製造方法
DK2599784T3 (en) Nucleotide AND / OR oligonucleotide AND MANUFACTURING METHOD THEREOF
US20040266996A1 (en) Methods of manufacture of 2'-deoxy-beta-L-nucleosides
US20240287120A1 (en) Functionalized n-acetylgalactosamine analogs
EP2771343A1 (fr) Inhibiteurs de méthyltransférase pour traiter le cancer
WO2023249905A1 (fr) Compositions et procédés de synthèse d'oligonucléotides en phase liquide
JPWO2010150789A1 (ja) 核酸の合成法
CA3240651A1 (fr) Arn double brin, son procede de preparation et son utilisation
US12098371B2 (en) Lipid-pegylated compounds, preparations and uses thereof
US12116382B2 (en) Functionalized N-acetylgalactosamine analogs
US11897914B2 (en) Synthesis of 2′ protected nucleosides
WO2024137756A1 (fr) Composés et procédés de synthèse d'oligonucléotides en phase liquide

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20240301

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR